Lung cancer is the leading cause of cancer deaths in men and women in the United States with over 170,000 new cases annually. The five year survival rate of 15% has not changed appreciably over the last 20 years. Treatments designed to disrupt molecular pathways that mediate cancer cell proliferation and survival have shown promise for lung cancer treatment, and this proposal extends the concept of targeted treatment to a molecular pathway identified by the investigators. The goal of this proposal is to develop a novel molecularly targeted approach to treating metastatic lung cancer. The investigators will build on experience gained from the ongoing Phase I clinical trial of DOTAP:Chol FUS1 nanoparticle vector in patients with refractory stage IV non-small cell lung cancer. We will develop a tumor-selective expression system using the hTERT modified promoter and combine an imaging moiety in our therapeutic vector system to allow real-time imaging of vector biodistribution in humans. The investigators were informed by FDA that it will not be necessary to file a new IND for the modified plasmid. The changes in the DOTAP:Chol FUS1 construct will be acceptable with a single species toxicology study as proposed in this application. Therapeutic studies in vivo and imaging studies will take 12 months. The toxicology study will take 8 months to complete and will be done simultaneously with the therapy studies. Thus the proposed timeline is realistic and will lead to initiation of a randomized clinical trial in the Phase II STTR. The aims of this proposal are: Specific Aim 1: Evaluate the therapeutic effect of the FUS1 tumor suppressor gene and the mechanism of action in vivo. The therapeutic potential of FUS1 and its underlying mechanism of action will be determined by assessing the efficacy of tumor growth inhibition in human lung cancer xenograft mouse models as well assessing tumor tissues for FUS1 gene expression and induction of apoptosis in vivo. Specific Aim 2: Develop imaging technologies in mice for evaluation of biodistribution and therapeutic efficacy on FUS1 SSRT2A -nanoparticles. In this study, we will focus on developing and evaluating a novel tumor-specific hTMC promoter-driving SSRT2A-FUS1 dual molecular imaging reporter and therapeutic gene expression vector system. The hTMC promoter combines the tumor selective properties of the hTERT promoter with the strong transcriptional activity of the CMV IE promoter. This will be combined with sensitive gamma camera imaging with an 111In-Octreotide probe to evaluate biodistribution, expression, and tumor suppressing activity of FUS1-mediated molecular therapy in a human lung cancer mouse model. Specific Aim 3: To conduct toxicology studies for FDA regulatory filing. The primary goal of this aim is to conduct toxicology studies in mice. The goal of this proposal is to develop a novel molecularly targeted approach to treating metastatic lung cancer. The investigators will build on experience gained from the ongoing Phase I clinical trial of DOTAP:Chol FUS1 nanoparticle vector in patients with refractory stage IV non-small cell lung cancer. We will develop a tumor-selective expression system using the hTERT modified promoter and combine an imaging moiety in our therapeutic vector system to allow real-time imaging of vector biodistribution in humans. [unreadable] [unreadable] [unreadable]